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Transcriptional targets of hepatocyte growth factor signaling and Ki-ras oncogene activation in colorectal cancer

Oncogene volume 25, pages 91–102 (2006)Cite this article

Abstract

Both Ki-ras mutation and hepatocyte growth factor (HGF) receptor Met overexpression occur at high frequency in colon cancer. This study investigates the transcriptional changes induced by Ki-ras oncogene and HGF/Met signaling activation in colon cancer cell lines in vitro and in vivo. The model system used in these studies included the DLD-1 colon cancer cell line with a mutated Ki-ras allele, and the DKO-4 cell line generated from DLD-1, with its mutant Ki-ras allele inactivated by targeted disruption. These cell lines were transduced with cDNAs of full-length Met receptor. Microarray transcriptional profiling was conducted on cell lines stimulated with HGF, as well as on tumor xenograft tissues. Overlapping genes between in vitro and in vivo microarray data sets were selected as a subset of HGF/Met and Ki-ras oncogene-regulated targets. Using the Online Predicted Human Interaction Database, novel HGF/Met and Ki-ras regulated proteins with putative functional linkage were identified. Novel proteins identified included histone acetyltransferase 1, phosphoribosyl pyrophosphate synthetase 2, chaperonin containing TCP1, subunit 8, CSE1 chromosome segregation 1-like (yeast)/cellular apoptosis susceptibility (mammals), CCR4–NOT transcription complex, subunit 8, and cyclin H. Transcript levels for these Met-signaling targets were correlated with Met expression levels, and were significantly elevated in both primary and metastatic human colorectal cancer samples compared to normal colorectal mucosa. These genes represent novel Met and/or Ki-ras transcriptionally coregulated genes with a high degree of validation in human colorectal cancers.

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Acknowledgements

We thank Drs S Shirasawa and T Sasazuki for making available the DLD-1 and DKO-4 cell lines, James Ho for assistance in immunohistochemistry, Dr Runjan Chetty (Department of Pathology, UHN) for assistance in quality control of tissues used for realtime RT–PCR studies. We also thank James Jonkman and the Advanced Optical Micro-imaging Facility (AOMF) at OCI for invaluable advice and assistance in fluorescence image quantification, and Wendy Zhang for assistance in analysis of publicly available microrarray databases. The authors thank Richard Lu, David Otasek and Baiju Devani for their help in developing OPHID database and its search engine, network visualization software and web interface. We gratefully acknowledge the hardware and software support from IBM Life Sciences through a Shared University Research Grant. Grant Support: Canadian Institutes of Health Research (CIHR) grant MOP-64345; National Science and Engineering Research Council (RGPIN 203833-02), Institute for Robotics and Intelligent Systems, Precarn Incorporated and IBM to IJ; CIHR Doctoral Research Award to IMS-L; Precarn Scholarship to KRB.

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Authors and Affiliations

  1. Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada

    I M Seiden-Long, K R Brown, W Shih, N Radulovich, I Jurisica & M-S Tsao

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    I M Seiden-Long, K R Brown, I Jurisica & M-S Tsao

  3. Department of Surgery, University of Toronto, Toronto, Ontario, Canada

    D A Wigle

  4. Department of Computer Science, University of Toronto, Toronto, Ontario, Canada

    I Jurisica

  5. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    M-S Tsao

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  1. I M Seiden-Long
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Correspondence to M-S Tsao.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Seiden-Long, I., Brown, K., Shih, W. et al. Transcriptional targets of hepatocyte growth factor signaling and Ki-ras oncogene activation in colorectal cancer. Oncogene 25, 91–102 (2006). https://doi.org/10.1038/sj.onc.1209005

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